Methods for venous occlusion for the treatment of venous insufficiency

ABSTRACT

Methods, devices and systems are described for treating venous insufficiency in which the vein is compressed at least partially along a treatment zone. A system can be provided including an injection device, such as a glue gun, that is operably connected to a delivery catheter that can be advanced across a treatment zone in the vein. The delivery catheter can be used to deliver one, two, or more boluses of media (e.g., cyanoacrylate) to occlude the vein along different spaced-apart sections of the treatment zone. External compression can also be applied to the vein by a compression element, such as a hand or multifunctional ultrasound transducer, to occlude portions of the vein along the treatment zone prior to or during the introduction of the boluses of media.

PRIORITY CLAIM

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional App. Nos. 61/154,322 filed on Feb. 20, 2009 and 61/285,926filed on Dec. 11, 2009. This application also claims priority under 35U.S.C. §120 as a continuation-in-part application of PCT App. No.PCT/US2010/024820 filed on Feb. 19, 2010, which in turn claims priorityto U.S. Provisional App. Nos. 61/154,322 filed on Feb. 20, 2009 and61/285,926 filed on Dec. 11, 2009. Each of the priority applications ishereby incorporated by reference in its entirety.

BACKGROUND

Healthy leg veins contain valves that allow blood to move in onedirection from the lower limbs toward the heart. These valves open whenblood is flowing toward the heart, and close to prevent venous reflux,or the backward flow of blood. When veins weaken and become enlarged,their valves cannot close properly, which leads to venous reflux andimpaired drainage of venous blood from the legs. Venous reflux is mostcommon in the superficial veins. The largest superficial vein is thegreat saphenous vein, which runs from the top of the foot to the groin,where it originates at a deep vein.

Factors that contribute to venous reflux disease include female gender,heredity, obesity, lack of physical activity, multiple pregnancies, age,past history of blood clots in the legs and professions that involvelong periods of standing. According to population studies, theprevalence of visible tortuous varicose veins, a common indicator ofvenous reflux disease, is up to 15% for adult men and 25% for adultwomen. A clinical registry of over 1,000 patients shows that the averageage of patients treated for venous reflux is 48 and over 75% of thepatients are women.

Venous reflux can be classified as either asymptomatic or symptomatic,depending on the degree of severity. Symptomatic venous reflux diseaseis a more advanced stage of the disease and can have a profound impacton the patient's quality of life. People with symptomatic venous refluxdisease may seek treatment due to a combination of symptoms and signs,which may include leg pain and swelling; painful varicose veins; skinchanges such as discoloration or inflammation; and open skin ulcers.

A primary goal of treating symptomatic venous reflux is to eliminate thereflux at its source, such as, for example, the great saphenous vein. Ifa diseased vein is either closed or removed, blood can automaticallyreroute into other veins without any known negative consequences to thepatient.

The current non-invasive methods for treatment of reflux in the greatersaphenous vein include radiofrequency (RF) ablation, laser endothermalablation, and sclerotherapy, including foam sclerotherapy.Radiofrequency ablation and laser ablation require tumescent anesthesiawhich produce both bruising and pain along the inner thigh and upperinner calf for several weeks, and both can have side effects of burnsand nerve damage. Radiofrequency ablation and laser ablation alsorequire capital purchases of a radiofrequency device or laser box, oftenat costs of more than $50,000, in addition to expensive disposalmechanisms. While foam sclerotherapy is relatively non-invasive, it hasa high rate of recurrence and potential side effects. All of the methodsrequire wearing compression stockings for 2-4 weeks.

SUMMARY

Disclosed herein is a method of treating a vein, comprising the stepsof: advancing a catheter distally across a treatment zone in a vein;creating a first occlusion in the vein at a distal end of the treatmentzone; introducing a first bolus of media into the vein against aproximal side of the first occlusion; creating at least a secondocclusion in the vein, spaced proximally apart from the first occlusion;introducing a second bolus of media into the vein against a proximalside of the second occlusion; and withdrawing the catheter from thevein.

Also disclosed is a method of treating a vein, comprising the steps of:creating an occlusion in a vein; positioning the distal end of acatheter to define a first volume within the vein between the occlusionand the catheter; and introducing a second volume of media from thecatheter into the vein; wherein the second volume is at least about 110%of the first volume.

In another embodiment, disclosed is a method of treating a vein,comprising the steps of creating an occlusion in a vein; positioning thedistal end of a catheter within the vein, the catheter having a distalopening and a side wall; and introducing media through the distalopening in a volume sufficient to advance proximally around the catheterbetween the sidewall of the catheter and the wall of the vein.

Further disclosed is a system for treating a vein, comprising: aninjector for delivering a vein-occluding substance into a vein. Theinjector can be operably connected to a control. Activation of thecontrol results in the injector delivering a bolus of between about 0.05mL and 3 mL of the vein-occluding substance into the vein. The system isconfigured to deliver a plurality of spaced-apart boluses of thevein-occluding substance. Also included in the system is a catheterhaving a distal opening and a side wall, the catheter configuredoperably to be connected to the injector, wherein the catheter isconfigured to advance distally across a treatment zone in the vein. Theinjector can include a glue gun, which may also include an adapter,which can be as described below. The catheter can include a luer lockfor operable connection to the injector. The system can also include avolume of vein-occluding substance, such as between about 1 mL to 20 mLof vein-occluding substance in some embodiments. The vein-occludingsubstance could be cyanoacrylate, and further include a compressionelement configured to externally compress the vein. The control can beconfigured to actuate the injector to introduce media through the distalopening in a volume sufficient to advance proximally around the catheterbetween the sidewall of the catheter and the wall of the vein. Thesystem can also include an occluder comprising a frame portion and abarrier portion, examples of which are described further in detailbelow.

In another embodiment, disclosed is a system for treating a vein, thatincludes a catheter comprising a proximal opening, a distal opening, anda sidewall, the catheter configured to deliver a vein-occludingsubstance within a vein, the catheter having a length sufficient toextend from a distal superficial leg vein to the superficial femoralvein junction; a sheath configured to house the catheter at leastpartially therethrough, the sheath having a length of from about 25 cmto about 100 cm and an inside diameter of from about 3 French to about 7French; and an injector carrying a vein-occluding substance, theinjector operably connectable to the catheter and comprising a control,wherein actuation of the control causes injection of a predeterminedvolume of vein-occluding substance, wherein the predetermined volume ofvein-occluding substance is between about 0.05 mL and 0.5 mL.

In yet another embodiment, discloses is a catheter comprising a proximalopening, a distal end having a distal opening, and a sidewall, thecatheter configured to deliver a vein-occluding substance within a vein,the catheter having a length sufficient to extend from a distalsuperficial leg vein to the superficial femoral vein junction; a sheathconfigured to house the catheter at least partially therethrough, thesheath having a length of from about 25 cm to about 100 cm; and aninjector carrying a vein-occluding substance, the injector operablyconnectable to the catheter and comprising a control, wherein actuationof the control when the distal end of the catheter is positioned withinthe vein proximal to an occlusion in the vein causes injection of apredetermined volume of vein-occluding substance into the catheter andout the catheter distal opening, wherein the predetermined volume issufficient to advance the vein-occluding substance proximally around thecatheter between the sidewall of the catheter and the wall of the vein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-11 schematically illustrate a method for occluding a vein, suchas the great saphenous vein, using a vein-occluding substance and animaging tool, according to one embodiment of the invention.

FIGS. 12-16 schematically illustrate a method for occluding a vein, suchas the great saphenous vein, according to another embodiment of theinvention.

FIGS. 17-21E schematically illustrate methods for occluding a vein, suchas the great saphenous vein, according to another embodiment of theinvention.

FIGS. 22-32 illustrate various views and components of a vein-occludingdispensing system according to some embodiments of the invention.

FIGS. 33-34 schematically illustrate a glue gun and adapter assembly.

FIG. 35 schematically illustrates a front view of a glue gun, accordingto one embodiment of the invention.

FIG. 36 illustrates schematically major components of a vascularocclusion system, according to one embodiment of the invention.

FIGS. 37A-37D illustrate various views of a vascular occlusion device,according to one embodiment of the invention.

FIGS. 38A-38D illustrate various views of the occlusion device of FIGS.2A-2D in an expanded configuration.

FIGS. 39A-39B illustrate an embodiment of the frame portion of thedelivery device described above in connection with FIGS. 2A-3D with thebarrier portion omitted for clarity.

FIG. 40 is a side cross-sectional view of an occlusion device in anexpanded configuration and implanted within a vessel, according to oneembodiment of the invention.

FIG. 41 is a cross-sectional view of an occlusion device in anundeployed configuration within a delivery catheter, according to oneembodiment of the invention.

FIGS. 42-44 illustrate perspective, cross-sectional views of anocclusion device in varying stages of deployment out of a deliverycatheter, according to one embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are systems, methods and devices for the minimallyinvasive treatment of varicose veins and other medical conditions. Whenused herein with respect to the device, proximal can refer to toward theaccess insertion site into a blood vessel, while distal refers to awayfrom the access insertion site and in the direction of the patient. Insome embodiments an occlusive device is deployed to block the saphenousvein just distal to the Superficial Femoral Vein Junction (SFJ) andcreate a flattened shape so the vein can be treated further using eithera substance to alter the vein such that blood flow is prevented therein,such as sclerosing solution or medical adhesive. In some embodiments,complete vein closure is the desired clinical result of all treatmentsto mitigate the effects of venous hypertension caused by retrogradevenous flow. The occlusion device and medical adhesive can be deliveredthrough a catheter utilizing a “single stick” method. This approach isdesigned to produce less pain and fewer skin injections than used incurrent treatment approaches, as well as to mitigate or eliminate theneed for patients to wear uncomfortable compression stockings aftertreatment.

Vein-Collapsing Methods

Methods to treat venous insufficiency are now described, in which thevein is compressed at least partially along the treatment zone. Doing socan better ensure that the vein is partially or fully collapsed asopposed to merely occluded, depending on the desired clinical result.Not to be limited by theory, collapsing the vein may place two or moreluminal surfaces of endothelial cells into opposing contact with eachother, stimulating fibrous tissue proliferation and resulting inimproved long-term closure of the vein with a lower risk ofrecanalization and vein re-opening. In some embodiments, a deploymentcatheter is percutaneously introduced into a vein at an access site, andtranslumenally distally advanced across a treatment zone within a vein.External compression is applied to collapse the vein distally of thedeployment catheter. Then the distal end of the catheter advances to thevery beginning of the occluded vein at the proximal side of theocclusion to minimize the “trapped” blood between the catheter and theoccluded vein. After a bolus of plug forming media is expressed from thedistal end of the catheter, the occlusion at the end of the catheterforces the vein-occluding substance to flow retrograde (proximally)toward the catheter insertion point into the vein and reduce the distalflow force and mixing with blood within the vessel. This method alsoallows the vein-occluding media to replace any existing blood “trapped”between the catheter and the occluded vein and forms an occlusive plugwithin the vein while minimizing mixing with the blood. This reductionin mixing can be advantageous in certain embodiments because it canincrease the bonding strength between the vein-occluding media and thevein. External compression distally to the treatment zone optionally maybe removed, or may remain throughout all or a portion of the procedure.External compression can also occur around the area of the vein wherethe plug forming media is expressed in order to collapse the vein asnoted above. The catheter is thereafter proximally retracted whiledispensing a vein occluding substance, either continuously or viadiscrete boluses spaced apart from the initial bolus at regular orirregular intervals across the treatment zone. External compression cancontinue proximally where the vein occluding substance is beingdispensed in order to ensure collapse of the vein as noted above. Thecatheter is thereafter withdrawn, and the access site closed usingconventional techniques. The method is described in greater detailbelow.

The vein closure system can enter the vein such as the greater saphenousor lesser saphenous vein or other vessel using fluoroscopy, ultrasound,or other guidance means. A micro-catheter system can be placed over awire for introduction of an outer catheter or introduction sheath intothe vein. In some embodiments, the vein is entered as distal as possibleor as clinically relevant in the abnormal vein. In some embodiments, theclosure method comprises advancement of an introducing sheath and/ordilator over a guide wire to the sapheno-femoral junction below theanterior-inferior epigastric vein, which in some embodiments, can beapproximately 1.5 to 2.5 cm from the sapheno-femoral junction. Followingplacement of the sheath to this level and optional verification withultrasound, an inner catheter is introduced through the sheath and isluer-locked or otherwise secured to the sheath to maintain a fixedposition with the tip extending approximately 5 cm from the end of thesheath.

In accordance with FIG. 1, the occlusion method comprises providing aninjector such as a glue gun 300 that assists in injecting avein-occluding substance to occlude vessel 400. In some embodiments, thedistal end 302 of the glue gun 300 includes a syringe that is operablyconnected to an inner catheter 204 by a leer lock 602. A sheath or outercatheter 202 surrounds the inner catheter 204, and assists in providingaccess to a target site within the vessel 400 interior. In someembodiments, the outer catheter 202 is introduced first followed by theinner catheter 204, while in other embodiments, the outer catheter 202and inner catheter 204 are introduced simultaneously. As shown in FIG.1, the outer catheter 202 and inner catheter 204 are introduced near theproximal end 402 of the vessel 400 and are directed towards the distalend 401 of the vessel, where the vein-occluding substance will bereleased. Inone embodiment, at the site of release of the vein-occludingsubstance, the inner catheter 204 will extend beyond the distal end ofthe outer catheter 202, such as by between about 3 cm and 7 cm, toprevent any vein-occluding substance from contacting the outer catheter202.

As shown in FIG. 1, an imaging tool such as an ultrasound transducer 630can also be provided that could be multifunctional, including guidingone or more catheters, serving as a compression element, and/oridentifying areas in the interior of the vessel that may need furtherocclusion or closure. In some embodiments, the ultrasound transducer 630can be placed into contact with an external surface of a patient's skinprior to placing the outer catheter 202 and/or inner catheter 204through the vessel 400. The ultrasound transducer 630 can assist ingenerating images to help guide one or more catheters to a site where avein-occluding substance will be introduced. In some embodiments, theultrasound transducer 630 can also serve as a compression element priorto, during or after introducing a vein-occluding substance to assist inclosure of the vessel 400. By serving as a compression element, theultrasound transducer can help to flatten and/or reduce the size of thevessel 400. In some embodiments, the ultrasound transducer 630 caninclude a Doppler flow detection capability, and help to identify areasin the interior of the vessel 400 that may need further closure orocclusion and thus, further application of a vein-occluding substance.

When the inner catheter is in position and verified with ultrasound tobe in the appropriate position below the sapheno-femoral junction,compression at the sapheno-femoral junction is performed and smallamounts of vein occluding substances, including liquid adhesives such asglues including cyanoacrylates, or any substances described elsewhereherein or known in the art, are injected into the vein. The vein canthen be collapsed using compression, such as external compression toassist in coating the vein and adhering the internal walls of the veinto the vein-occluding substance in a solid, permanent bond. In someembodiments, an additional compression device can be provided inaddition to the ultrasound transducer or probe (either proximally ordistally) to assist in collapsing the vein. In some embodiments, thecompression device can be a sequential compression device configured toapply compressive pressure from a compressor against the patient's limbthrough a flexible pressurized sleeve. The compression can be configuredto deliver uniform compression along its length, distal-to-proximalcompression in a peristaltic wave or other modes depending on thedesired clinical result. In some embodiments, the compressive devicecould be configured to deliver a pressure of at least about 30, 40, 50,60, 70, 80, 90, 100, 125, 150, or more mm Hg, or between about 30-150 or50-100 mm Hg in some embodiments. In some embodiments, an externaldevice delivering energy to create a controlled vasospasm of the vein isused. The energy could be, for example, electrical stimulation,cryotherapy, infrared, visible, or UV light, microwave, RF energy,ultrasound energy, magnetic energy, thermal energy, or a combination ofthe energy sources.

In accordance with FIG. 2, the tip of the inner catheter 204 is placedat a site adjacent to the blocked or distal end 401 of the vessel 400with a minimum distance between them. Once the outer catheter 202 andinner catheter are in place, the glue gun 300 can inject avein-occluding substance 502 that is released from the inner catheter204. In some embodiments, the inner catheter 204 can release at least 1,2, 3, 4, 5, 7, 10, 12, 15, 20, or more boluses of vein-occluding mediaalong a treatment site within a vein. For example, in some embodiments,a single continuous flow of vein-occluding media can be introducedacross a treatment site, while in other embodiments, multiplespaced-apart boluses of vein-occluding media can be introduced atregular or irregular intervals across a treatment site. In someembodiments, the treatment site can be a total length of between 2 cmand 50 cm, or between about 5 cm and 40 cm in some embodiments. Alongthe treatment site, one or more boluses of vein-occluding media can beintroduced at spaced-apart intervals, such as between every 1 cm and 7cm, more preferably between every 3 cm and 5 cm. The intervals need notbe evenly spaced. Each bolus of media can occlude and treat at least aportion of the treatment site. In some embodiments, a single bolus ofmedia can occlude and treat a length of the vein that is between 0.5 cmto 5 cm, such that at least about 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, or 5cm of the vein can be treated. In other embodiments, the length of thetreatment site within the vein will be greater than 5 cm by a singlebolus of media. Providing one or more boluses of vein-occluding media,particularly in selected intervals, as described herein advantageouslyprovides a treatment that can be performed with greater control and easeover conventional vein-occluding processes and which can be tailored tospecific patients (e.g., having different lengths of treatment zones).

In some embodiments, each bolus of media can have a volume of between0.01 to 3 cc of a vein-occluding substance (e.g., cyanoacrylatecompound), such as between 0.01 cc to 1 cc of a vein-occludingsubstance. The rate of injection can be controlled manually, or by amechanical and/or electronic controller configured to release apre-determined volume of vein-occluding substance at a specified flowrate. While in some embodiments the injection rate can be relativelyconstant throughout the procedure in some embodiments, in otherembodiments, the injection rate can be variable, releasing periodicboluses of vein-occluding substance at specified time and/or distanceintervals. In some embodiments, the injection rate is between 0.002cc/sec and 6 cc/sec, such as between about 0.02 cc/sec and 0.2 cc/sec.Controlling the volume and flow rate of the bolus of media to levelsdescribed herein advantageously prevents unnecessary overflow orundertreatment of the media within the vein. In some embodiments, aninjector is provided that is configured to precisely deliver apredetermined volume of media, such as between about 0.05 mL and 0.5 mL,or between about 0.1 mL and 0.2 mL, into the vein when a physicianactuates a control, such as a button, switch, dial, or foot pedal, forexample. In some embodiments, the injector includes a safety feature,such as an electronic lockout that prevents unintended multiple bolusinjections of glue within a specified period of time, such as, forexample, requires that bolus injections be spaced apart by at leastabout 0.5, 1, 2, 3, 4, 5 seconds, or more.

In accordance with FIG. 3, once the vein-occluding substance 502 isinjected out of the tip of the inner catheter 204, the vein-occludingsubstance 502 flows against the distal end of the proximal side of theoccluded vessel 400 and then reverses flow proximally traveling alongthe outside of the catheter track while displacing the blood contentalong the target area of the vessel 400. Then, the outer catheter 202and inner catheter 204 can be pulled back or withdrawn to target adifferent site along the vessel 400. For example, the outer catheter 202and inner catheter 204 can be moved in a direction towards the proximalend 402 of the vessel 400 prior to injecting additional vein-occludingsubstance 502 into the vessel 400.

In accordance with FIG. 4, an optional compression element, e.g., anoperator's hand 640, a sequential compression device, or the ultrasoundtransducer 630 can be used to apply pressure on the external surface ofthe patient's body and compress the interior walls of the vessel 400.The optional compression element can be used to compress portions of thevessel prior to, during or after the introduction of the vein-occludingsubstance. When the compression element compresses portions of thevessel during or after the introduction of the vein-occluding substance,the vessel is compressed against the vein-occluding substance 502, asshown in FIG. 4. This compression assists in occlusion as well ascollapse of the vessel. In some embodiments, as additional portions ofthe vessel are treated with the vein-occluding substance, the targetregions can be compressed immediately following, or no more than about 5minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, 30 seconds, 15seconds, or less following injection of the vein-occluding substance insome embodiments.

FIGS. 5-6 illustrate the ultrasound transducer 630 guided or moved froma first location to a second location following injection of thevein-occluding substance 502 at the first site. Once the vein-occludingsubstance 502 is injected to a targeted site and preferably, once thevein is completely occluded and/or collapsed at that site, theultrasound transducer 630 can be moved to a second location, e.g., alocation closer towards the proximal end 402 of the vessel 400, toassist in collapse of the vessel 400 at a different site. In someembodiments, by moving the ultrasound transducer 630 along the length ofthe vessel 400 in a proximal direction, the ultrasound transducer canserve as a compression element that provides a compression that followsthe length of the vessel 400 in a proximal direction to better ensurecollapse of the vessel. In some embodiments, the ultrasound transduceror other external compression element can be moved a distance betweenthe first location to a second location spaced apart between 0.5 cm to 5cm with respect to the first location. In other embodiments, theultrasound transducer can be moved a distance between the first locationto a second location that is between 3% and 50%, such as between 3% and20% of the total length of the treatment site. Guiding the ultrasoundtransducer over a discrete distance advantageously helps to ensure thatportions of the treatment site are effectively occluded before guidingthe ultrasound transducer over different portions of the treatment site.After moving the ultrasound transducer 630, the glue gun 300 can injecta vein-occluding substance 502 at the different site of the vessel 400,as shown in FIG. 6.

Once the vein-occluding substance 502 is injected into the second siteof the vessel 400, a compression element e.g., the hand 640, can onceagain be used to assist in collapse of the portion of the vessel 400, asshown in FIG. 8. After achieving partial or complete closure of aportion of the vessel 400, the ultrasound transducer 630 can once againbe guided or moved along the vessel 400 to different locations to assistin closure or occlusion of the vessel 400, providing a moveablecompression element in some instances. With the assistance of theultrasound transducer 630 and/or additional compression element asdescribed above, which can move along the length of the vessel 400 andserve as a compression element and/or image generator, it is possible tocollapse the vessel 400 along the entire treatment length. As shown inFIG. 9, the ultrasound transducer 630 is guided to the second locationalong the vein 400 to assist in collapse of the vessel 400 at thedifferent location.

The application of the ultrasound probe and/or additional compressiondevice can be repeated at multiple locations along the greater saphenousvein, as shown in FIGS. 10-11, until the vein is partially or entirelyco-apted and closed in a flattened state. The inner catheter can then beremoved, and a band-aid or other dressing can be placed over theentrance site. In some embodiments, the ultrasound probe can generateimages that reconfirm the closure or co-apting of the flattened vein.Once the flattened vein is closed partially or completely, the injectoris removed from the access site, and the procedure then is completed. Inone embodiment, only a small amount of local anesthesia at the entrancesite is used. No tumescent anesthesia is required. No general orconscious sedation is required as the procedure produces no significantheat or other types of damage to surrounding tissues.

While the methods above have been described with the intention ofoccluding the great saphenous vein, a wide variety of other veins,arteries, lymphatics, or other body lumens, natural or artificial can beoccluded as well using systems and devices as disclosed herein.Furthermore, a variety of conditions can be treated with the systems,devices, and methods disclosed herein, for example, venousinsufficiency/varicose veins of the upper and/or lower extremities,esophageal varices, gastric varices, hemorrhoidal varices, venous lakes,Klippel-Trenanay syndrome, telangiectasias, aneurysms, arterio-venousmalformations, embolization of tumors or bleeding vessels, lymphedema,vascular and non-vascular fistulas, closure of fallopian tubes forsterilization, etc.

In some embodiments, the vein-occluding substance can be injected intothe vein using an automated process in order to minimize undesiredover-injection or under-injection of the vein-occluding substance,injection at undesired intervals or injection of undesired bolus sizes.For example, the outer catheter member of the catheter can be madeeasily compressible (e.g., with a thin wall). The column strength neededfor catheter placement can thus be supplied predominantly with the innertube. Once the inner catheter has been withdrawn from the vein, theremaining outer catheter is filled with the vein-occluding substance.The proximal end of the outer catheter just distally of the luer lock,manifold, or other coupling to the vein-occluding substance injector cancarry a compression element such as a clamp, parallel rollers, or aslideable element with the catheter extending transversely between twoportions of the slideable element. Actuating the compression elementwill radially compress the outer catheter. An operator can then hold theclamp in place while the catheter is pulled proximally through theclamp. The clamp thus slides, rolls, or otherwise moves along the tube,while the catheter is compressed to precisely express the volume of thecatheter as a function of the distance the catheter is withdrawnproximally from the vein.

FIGS. 12-16 schematically illustrate a method for occluding a vein, suchas the great saphenous vein, according to one embodiment of theinvention. Ultrasonographic vein mapping, contrast venography, or othertechnique, for example, can be used prior to the occlusion procedure tobetter visualize a patient's particular vascular anatomy in someembodiments. The entry site is prepped and draped in a sterile fashion,and local anesthesia such as Lidocaine can be provided, although may notbe required. First, the vascular system, such as a superficial vein inthe foot, ankle, or calf, for example, a dorsal digital vein,intercapitular vein, common digital vein, dorsal venous arch, medialmarginal vein, lateral marginal vein, plantar cutaneous venous arch, ora vein of the plantar cutaneous venous network is cannulated, such aspercutaneously or alternatively through a cut-down procedure. Any ofthese veins can also be occluded using the systems and methods describedherein. Imaging such as ultrasound or fluoroscopy, for example, can beused for access assistance. A guidewire (not shown) can then be insertedinto the vessel. A sheath or introducer, such as a needle, can also beplaced to facilitate catheter entry into the appropriate vein. Next, adelivery catheter 200, including inner catheter member and outercatheter member, as well as housing an occlusion device such asdescribed above can be inserted into the vessel as shown in FIG. 12 via,for example, the Seldinger technique over a guidewire. The catheter 200is then advanced distally into the venous system to a desired location,such as within the great saphenous vein (or small saphenous vein oraccessory saphenous vein) as shown in FIG. 13. The inner catheter canthen be actuated relative to the outer catheter to deploy an occlusiondevice 100 to its expanded configuration within the desired locationwithin the vein 400. The occlusion device can in some embodimentsinclude components as described, for example, in U.S. ProvisionalApplication No. 61/154,322, filed on Feb. 20, 2009, and hereinincorporated by reference in its entirety, including (but not limitedto) those having tissue anchors or bars or other features for engagingvessel walls. In some embodiments, the occlusion device can includecomponents as described with respect to FIGS. 36-44. FIG. 14 illustratesthe inner catheter being advanced in preparation to deploy an occlusiondevice 100. Once desired placement is confirmed, the detachmentmechanism such as a suture (not shown) is then actuated to release theocclusion device 100 within the vessel. Deployed anchors on the frameportion of the occlusion device 100, can prevent migration of theocclusion device 100 from the desired location within the vein 400.Next, the inner catheter can be withdrawn, as illustrated in FIG. 15.

After withdrawal of the inner catheter, a vein-occluding substance suchas described above can be injected through the outer catheter into thevein 400 proximal to the deployed occlusion device. As illustrated inFIG. 16, the outer catheter can then be withdrawn while thevein-occluding substance continues to be injected, in order to occludethe vein in a proximal direction relative to the occlusion device. Theouter catheter can then be fully withdrawn, and an external compressionstocking applied, completing the procedure. Percutaneous closure methodscan also be utilized in some embodiments. In some embodiments, 0.01 ccto 1 cc of vein-occluding substance, e.g., a cyanoacrylate compound, canbe injected over a distance of 0.5 cm to 5 cm of vein, such as at leastabout 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm of vein to be treated. Theinjection rate can be relatively constant throughout the procedure insome embodiments, or variable, releasing periodic boluses ofvein-occluding substance at specified time and/or distance intervals.Withdrawal through the vein to be treated can take place, for example,over a period of 30 seconds to 5 minutes in some embodiments, or aboutequal to, or less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 minute, 45seconds, or 30 seconds in some embodiments.

A method of occluding a vein utilizing a vein-occluding substance as anoccluding member according to some embodiments will now be described infurther detail. First, a catheter can be deployed to a desired locationin a tubular structure such as a vein as illustrated and described inconnection with FIGS. 12 and 13 above. The vein 400 can then optionallybe compressed, either before or after placing the catheter, such as by,for example, external manual compression of the leg or with a tourniquetor other type of compression device at a distal location as shownschematically with arrows in FIG. 17. Next, a vein-occluding substancecan be injected at a first location within the vein 400 to serve as anoccluder 500, as shown in FIG. 18, to prevent embolization moredistally. External compression prior to and at a location just distal tothe injection site can advantageously help to prevent migration of theformed in situ occluder 500 prior to polymerization or other fixationprocess. Compression can also prevent unwanted embolization distallyinto more central veins, as well as induce retrograde flow of thevein-occluding substance proximally when the vein-occluding substance,upon distal ejection from the catheter, contacts the vein at the pointthat is collapsed from compression, forcing the vein-occluding substanceto flow proximally. In some embodiments, the distance from the exit porton the catheter where the vein-occluding substance is ejected to thearea of the vein that is collapsed from compression is no more thanabout 3 cm, 2.5 cm, 2 cm, 1.5 cm, 1 cm, 0.75 cm, 0.5 cm, 0.25 cm, orless.

The vein-occluding substance serving as an occluder 500 can be, forexample, a larger-volume bolus of a vein-occluding substance compared toa volume of vein-occluding substance injected more proximally over aspecified period of time and/or length of vein, of which specific rangesare described above. The initial bolus can be at least about 0.1 cc,0.25 cc, 0.5 cc, 0.75 cc, 1 cc, 1.5 cc, or more in some embodiments, orbetween about 0.05 mL and about 0.9 mL, between about 0.05 mL and about0.5 mL, or between about 0.1 mL and about 0.2 mL in other embodimentsThe initial bolus can be at least about 10%, 25%, 50%, 75%, 100%, 150%,200%, or more greater than a volume of vein-occluding substance injectedmore proximally over a similar length of vein.

In addition to, or instead of a large bolus volume of vein-occludingsubstance as described above, a second vein-occluding substance withdifferent properties than a first vein-occluding substance used to treatthe vein more proximally can also be used as an occluder. The secondvein occluding substance is deployed first, to form the distal veinblock. The first vein occluding substance is then dispensed along thelength of the treatment site as the catheter is proximally retracted.

The second vein-occluding substance can be, for example, a glue or otherocclusive medium that expands to a greater volume, hardens more rapidly,and/or has a shorter polymerization time relative to the firstvein-occluding substance. In some embodiments, the second vein-occludingsubstance can be partially or completely bioresorbable. If multipledifferent vein-occluding substances are used, the catheter can beconfigured to have two or more lumens to accommodate delivery of thedifferent vein-occluding substances. Alternatively the first and secondoccluding substances can be deployed sequentially via a common lumen.

When the vein-occluding substance serving as a distal occluder hardenssuch that a plug 500 is formed to completely prevent blood flow distallyas shown in FIG. 19, the catheter 200 can be withdrawn and the same or adifferent vein-occluding substance 502 as described above can beinjected along the length of the vein segment to be treated to occludethe rest of the vein 400 to be treated while the catheter is withdrawnpartially, and fully proximally as shown in FIGS. 20-21, respectively.As illustrated in FIG. 21, in some embodiments, 2, 3, 4, or more veins(that may be in some cases a branch of the first vein) can be treatedduring the procedure using a single puncture, or with 2, 3, 4, or morepunctures.

Thus, in accordance with one implementation of the present invention, adeployment catheter 200 is percutaneously introduced into a vein at anaccess site, and translumenally distally advanced across a treatmentzone within a vein. External compression, such as manual compression, isapplied to collapse the vein distally of the deployment catheter andcreate a first occlusion. A bolus of plug forming media is expressedfrom the distal end of the catheter against a proximal side of the firstocclusion, to form an occlusive plug 500 within the vein. Externalcompression optionally may be removed, or may remain throughout theprocedure. The catheter 200 is thereafter proximally retracted whiledispensing a vein occluding substance 502 across the treatment zone,either continuously as a long stream, or intermittently at spaced apartintervals, where a second occlusion in the vein can be created, spacedapart from the first occlusion, and then a second bolus of media isintroduced against the proximal side of the second occlusion Externalcompression may be applied proximally, anywhere along the length of thevein, to ensure complete filling of the vein with the vein occludingsubstance 502. In some embodiments, a second, third, or more boluses ofplug-forming media are progressively released into the vein moreproximally at desired intervals, and external compression can be appliedjust distal to the point in which the catheter releases the plug formingmedia as described above. The catheter 200 is thereafter withdrawn, andthe access site closed using conventional techniques.

FIG. 21A illustrates a vein 400 that is compressed distally at point 440to create a first occlusion, such as with external compression. Alsoshown is catheter 200 with distal end 201. After the creation of anocclusion 440 in a vein, a first volume V1 within the vein 400 can bedefined between the distal end 201 of the catheter 200 and the occlusion440, as illustrated in FIG. 21B. Media having a second volume V2, suchas in a bolus, can then be injected from the distal end 201 of thecatheter 200 into the vein 400. In some embodiments, the second volumeV2 (of the media injected) is at least about 100%, 105%, 110%, 120%,125%, 130%, 140%, 150%, 175%, 200%, 250%, or more of the first volume V1(of the vein in between the occlusion and the distal end of thecatheter), such that a proximally advancing meniscus of media V2 passesproximally past the distal end 201 of the catheter 200, as illustratedin FIG. 21C. The catheter 200 is then withdrawn proximally, asillustrated in FIG. 21D, and a second more proximal occlusion 440′ canbe created, such as via external compression. Media can then be injectedto create a volume of media V2′ greater than the volume within the vein400 between the distal end 201 of the catheter 200 and the occlusion440′, as illustrated in FIG. 21E. The process can then be repeated for atotal of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times depending onthe desired clinical result.

In some embodiments, an occlusion in a vein can be created as describedherein. A deployment catheter having a distal opening and side wall isprovided. The distal end of the deployment catheter can be positionedwithin the vein at the desired location. Media can then be introducedthrough the distal opening in a volume sufficient to advance proximallyaround the catheter between the sidewall of the catheter and the wall ofthe vein. In some embodiments, the volume sufficient to advanceproximally around the catheter between the sidewall of the catheter andthe wall of the vein is at least about 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL,0.5 mL, 0.7 mL, 0.8 mL, 1 mL, 1.5 mL, 2 mL, 3 mL, or more.

The distal plug 500 may be formed by a bolus of the same material asused for the vein occluding substance 502. Alternatively, the distalplug 500 may be formed from a material that polymerizes more rapidlythan vein occluding substance 502, or solidifies through a mechanismother than polymerization to form an occlusive plug. Plug 500 mayalternatively be formed by a self-expanding preformed material, such asa foam or woven or non-woven fiber based material, which may bedisplaced distally from the catheter such as by distally advancing apush wire, or utilizing the pressure of vein occluding substance 502.The self-expanding foam or other plug material 500 may be abioabsorbable material, so that no long term implant is left behind inthe body.

Proximal retraction of the deployment catheter 200 may be accomplishedin either a steady, continuous fashion, or in an intermittent, steppedmanner. Similarly, extrusion of vein occluding substance 502 may beaccomplished in a continuous manner as the catheter 200 is proximallyretracted. Alternatively, vein occluding substance 502 may be dispensedin a plurality of bolus ejections along the length of the treatmentzone, spaced apart by a predetermined or clinically determined distance.Spacing between adjacent injected volumes of vein occluding substance502 may be at least about 0.5 cm, at least about 1 cm, at least about 2cm, and, in some implementations, at least about 4 cm. This procedureminimizes the total volume of injected vein occluding substance 502,while providing a plurality of distinct bonding points along the lengthof the treatment zone.

Also disclosed herein is a method of obliterating a hollow structure,such as a vein, including the steps of reducing an interiorcross-sectional area of the hollow structure near the obliterating siteby applying a pressure to an exterior of the hollow structure; andplacing a catheter in the hollow structure and advancing it to theobliterating site, where the obliterating site is next to the reducedcross-sectional area. A medical adhesive can then be injected at theobliterating site. The interior cross-sectional area of the medicaladhesive at the obliterating site can then be reduced by compressing anexterior of the hollow structure to form an occlusion in the hollowstructure. Compression can be achieved, for example, via an imagingprobe such as an ultrasound transducer, manual pressure, or a harness.The medical adhesive can then solidify, forming an occlusion in thehollow structure. The method can also include the step of identifying anobliterating site prior to reducing an interior cross-sectional area ofthe hollow structure. In some embodiments, the catheter is removed fromthe obliterating site before compression.

With any of the methods and devices described herein, a wide variety ofvein-occluding substances can be used. In some embodiments, thesubstance can include an adhesive such as cyanoacrylate, e.g., 2-octylcyanoacrylate, and/or a sclerosing agent such as hypertonic saline,sodium tetradecyl sulfate, chromated glycerol, tetracycline, talc,bleomycin, or polydocanol. In some embodiments, a cyanoacrylate can bean aliphatic 2-cyanoacrylate ester such as an alkyl, cycloalkyl, alkenylor alkoxyalkyl 2-cyanoacrylate ester. The alkyl group may have from 1 to16 carbon atoms in some embodiments, and can be a C1-C8 alkyl ester or aC1-C4 alkyl ester. Some possible esters include the methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, cyclohexyl,heptyl, octyl, 2-methoxyethyl and 2-ethoxyethyl esters of cyanoacrylicacid. Other adhesives that can be used include a biological glue such asa bovine serum albumin-gluteraldehyde combination (e.g., BIOGLUE,Cryolife, Atlanta, Ga.), PVA, Biogard, collagen, fibrinogen,fibronectin, vitronectin, laminin, thrombin, gelatin, mixtures thereof,or other biocompatible adhesives. In some embodiments, a foam generatedfrom, for example, one or more of the above components can be used toenhance ablation and closure of the vein. The viscosity and air bubblemixture can also be controlled while taking into account the desiredclinical result.

In one embodiment, the chosen adhesive will not produce a significantthermal effect or significant local tissue abnormal effect, but ratherproduces an initial vessel co-aption/adhesion which will withstandphysiological venous pressures within the immediate post-procedureperiod. Since the adhesive will not produce a significant thermalreaction, no tumescent anesthesia is needed. In some embodiments, thechosen adhesive induces an inflammatory reaction which scars. Theinflammatory reaction can be followed by permanent closure of theabnormal greater or less saphenous vein. In some embodiments, the chosenadhesive is hardened after the first few moments (e.g., seconds orminutes) of application and therefore, compression stockings may not berequired. With the chosen adhesive, there can be minimal or no danger tosurrounding nerves or tissue. While the amount of chosen adhesivedelivered to a target site in a vessel will vary depending on the sizeof the vessel itself, in some embodiments, the amount of adhesive orother vein-occluding substance delivered in a single injection can bebetween about 0.05 mL and about 0.9 mL, between about 0.05 mL and about0.5 mL, or between about 0.1 mL and about 0.2 mL in other embodiments.In some embodiments, the amount delivered in a single injection could bemore than about 0.4 mL, 0.6 mL, 0.8 mL, 0.9 mL, 1 mL, or more. In someembodiments, the amount delivered in a single injection could be lessthan about 0.8 mL, 0.6 mL, 0.4 mL, 0.3 mL, 0.2 mL, 0.1 mL, 0.05 mL, orless.

In some embodiments, the cyanoacrylate preparation will contain anyadditives necessary to impart the desired properties to the preparationas viscosity, color, X-ray opacity, etc. Certain examples of additivessuch as thickening agents and polymerization inhibitors are discussedfurther below.

In some embodiments, the chosen adhesive can also be mixed with athickening agent, including various cyanoacrylate polymers,cyanoacrylate oligomers and biocompatible polymers. The biocompatiblepolymers can include, for example, PLA, PLLA, PGA, PCL, PDLLA, PLDGA,PMMA, PET, nylon, PE, PP, or PEEK, and in some embodiments, thebiocompatible polymers are soluble in a cyanoacrylate monomer. In someembodiments, the thickening agent can comprise glucose, sugar, starch orhydrogel. In some embodiments, the thickening agent can also comprisevarious particulates, ranging in size between about 0.001 microns to 100microns. The particulates can be provided in dry solid form and candisperse throughout a liquid adhesive to thicken the adhesive prior touse. In some embodiments, the particulate comprises any of thebiocompatible polymers above, such as PLA, PLLA, PGA, PCL, PDLLA, PLDGA,PMMA, PET, nylon, PE, PP, CAB and PEEK, while in other embodiments, theparticulate comprises a silica material with or without an acrylicpolymer. The thickening agent can assist in providing a suitableviscosity for the adhesive as it flows through the catheter to a targetsite.

In some embodiments, the chosen adhesive can also be mixed with one ormore polymerization inhibitors, which could be, for example, an anionicor a free-radical polymerization inhibitor. Anionic polymerizationinhibitors can include soluble acidic gases such as sulfur dioxide, or abiocompatible acid including, but not limited to, acetic acid, sulfuricacid, sulfonic acid, hydrochloric acid, phosphoric acid, carboxylicacid, nitric acid, or combinations thereof. In some embodiments, theacid can be from 0.01% to about 10% by weight, such as between about0.01% and 1% by weight. Free-radical polymerization inhibitors includehydroquinone, t-butyl catechol, hydroxyanisole, butylated hydroxyanisoleand butylated hydroxytoluene. The addition of one or more polymerizationinhibitors such as a biocompatible acid helps to change the curing rateof the adhesive to prevent the adhesive from sticking prematurely to thecatheter and prevent premature curing of the adhesive prior to bindingto the vein wall. In some embodiments, the acid helps to delay thecuring and/or polymerization of the adhesive to prevent the glue fromsticking to sections of the catheter.

One skilled in the art will appreciate that multiple compositions ofadhesive mixtures can be used in accordance with the embodimentsdescribed herein. In one embodiment, a composition of adhesive comprisesfrom about 0.01 to about 50.0 weight percent of cyanoacrylate polymer,from about 0.01 to about 50.0 weight percent of a thickening agentselected from the group consisting of cyanoacrylate polymer,cyanoacrylate oligomer and biocompatible polymers, and from about 0.01to about 10.0 weight percent of a biocompatible acid.

In some embodiments, the adhesive can also include a therapeutic agentsuch as an anti-inflammatory agent, an anti-infective agent, ananesthetic, a pro-inflammatory agent, a cell proliferative agent, orcombinations thereof.

In some embodiments, the medical adhesives, such as the cyanoacrylateadhesives, can have select properties. In some embodiments, the medicaladhesives can have a setting time of between about 5 to 60 seconds. Themedical adhesives can also have a viscosity of between about 40 to 3000cp. In some embodiments, the viscosity could be at least about 500 cp,at least about 1,000 cp, at least about 1,500 cp, at least about 2,000cp, at least about 2,500 cp, or more. In some embodiments, the viscositycould be no more than about 2,000 cp, no more than about 1,500 cp, nomore than about 1,000 cp, no more than about 500 cp, no more than about300 cp, or less. One skilled in the art will appreciate that the type ofadhesive is not limited to these particular characteristics, and thatother adhesives having different properties may also be applicable.

Additional Embodiments Related to the Vein Closure System

In additional embodiments, a vein closure system is described that doesnot require capital purchases for a radiofrequency device or laser box.Simple and non-invasive methods of using the vein closure system areprovided, and in some embodiments, the methods do not requireapplication of a tumescent anesthesia or wearing compression stockings.The acceptance by and demand from patients of the vein closure systemdescribed herein will be much higher over existing devices andtechniques.

In some embodiments, the closure system comprises at least two majorcomponents. One is a vein closure device which precisely delivers anadhesive to the abnormal saphenous vein under ultrasound guidance. Theother component is a unique intravascular adhesive which allows forco-aptation and closure of the abnormal saphenous vein in a flattened,closed position. In other embodiments, the closure system comprisesthree major components. The first is a vein closure device whichprecisely delivers an adhesive to the abnormal saphenous vein underultrasound guidance. The second is a unique intravascular adhesive whichallows for co-aptation and closure of the saphenous vein just distal tothe Superficial Femoral Vein Junction, such as within about 5 cm, 4 cm,3 cm, 2 cm, 1 cm, or less in a flattened, closed position. The third isa solution that can have adhesive and/or sclerosing properties whichallows for co-aptation and closure of the rest of the saphenous vein toalter the vein such that blood flow is prevented therein.

The Vein Closure Device

In some embodiments, the vein closure device which delivers thevein-occluding substance, e.g., an embolic adhesive, comprises threecomponents. The first component is an outer catheter or introducersheath that allows for placement under precise ultrasound guidance intothe saphenous vein from as low a position as possible in the greatersaphenous vein or lesser saphenous vein. The vein closure device is alsoconfigured for precise distal tip placement into the vein to beoccluded. In some embodiments, the sheath is available in multiple sizeranges and includes ID of 3 fr-7 fr and a length from 25 cm to 100 cmdepending on the placement site. In some embodiments, the sheath isechogenic under ultrasound observation and therefore can be preciselyplaced below the sapheno-femoral junction. The sheath can have multiplegraduations, as well measurement markings that indicate increments alongthe sheath, such as 0.2, 1, 2, or 5 cm increments. The graduations andmarkings assist in providing precise, monitored pull-back motions alongthe saphenous vein.

The second portion of the vein closure system is an introduction orinner catheter for the vein-occluding substance or adhesive. The innercatheter can be multiple sizes, such as from 3 fr-7 fr and includelengths of between about 25 cm to 100 cm to match the introductionsheath size ranges. In some embodiments, the inner catheter can belonger than the introduction sheath to allow the inner catheter toextend from a distal end of the introduction sheath. In one embodiment,both the inner catheter and the introducer sheath are made of materialssuch as PFTE, ePTFE, PFA, FEP, or similar polymeric materials that willprovide for negligible (if any) adhesion to the vein-occludingsubstance. In some embodiments, the inner catheter has an echogenic tipthat assists in advancement through the introducer sheath. The innercatheter can be attached to the introducer sheath, such as by leer lockor other locking mechanism. The inner catheter protrudes from theintroduction sheath at its distal end approximately 0.5-10 cm. and isvisible under ultrasound due to its echogenic tip. The inner catheter isused for precise delivery of a vein-occluding substance into the veinfor co-apting and occluding the vein into a flattened configuration. Insome embodiments, the outer catheter and/or inner catheter can becoupled to or extend from a syringe designed to dispense avein-occluding substance.

Glue Gun and Adapter

The third portion of the vein closure system is the glue gun or otheradhesive introducing device that attaches to the inner catheter. In someembodiments, the adhesive introducing device is a manual liquiddispenser gun that can dispense an adhesive into a vessel with controland accuracy. One such dispenser gun is disclosed in U.S. Pat. No.6,260,737 to Gruendeman et al., which is incorporated by referenceherein in its entirety. Other embodiments of the glue gun are discussedin more detail below.

Additional embodiments are provided that are directed to avein-occluding substance dispenser adapter, such as a glue gun, andassociated components. In some embodiments, a glue gun is provided thatis mateably attachable to a dispensing catheter or syringe by anadapter. The adapter can advantageously convert, for example, aconventional industrial glue gun for medical use, such as describedherein while being properly sterilized as well.

FIGS. 22-32 illustrate a glue gun system configured to assist in thedispensation of a vein-occluding substance, according to someembodiments of the invention. FIG. 22 illustrates a side view of a gluegun and adapter system including an adapter 1, a glue gun 2, and aplunger 3 according to one embodiment. The adapter 1 includes an adapterlock end 4 with collars or flanges 25 that allow the adapter 1 to befixed to the glue gun 2 via a holding segment 33. The adapter 1 furtherincludes a syringe lock end 5 that allows the adapter 1 to be fixed to asyringe 36.

The glue gun 2 includes a handle 31 and a pull trigger 12. The pulltrigger 12 is used in connection with internal mechanisms of the gluegun 2 (shown in FIGS. 33 and 34 and described further below) and theplunger 3 to provide controlled dispensation of a vein-occludingsubstance through syringe 36.

The plunger 3 comprises a solid rail-like segment that extends fromoutside the body of the glue gun 2 and through the internal body of theglue gun 2. The plunger 3 includes teeth that work in conjunction with aspring pawl mechanism (shown in FIG. 34) to lock the position of theplunger 3 and provide controlled dispensation of glue. The distal end ofthe plunger 3 makes contact with the proximal end of the syringe 36 suchthat the plunger 3 is capable of pushing the syringe to dispense avein-occluding substance such as an adhesive.

FIG. 23 illustrates a perspective view of the adapter 1 in FIG. 22. Theadapter 1 includes an adapter lock end 4, a syringe lock end 5, aholding slot 6 and a hollow body 7.

The adapter lock end 4 includes one or more collars or flanges 25 thatare receivable into a holding segment of the dispenser gun uponrotation. The adapter lock end 4 is configured such that upon rotationof the adapter 1, the flanges 25 are received in and secured in theholding segment 33. In addition, the adapter lock end 4 includes anopening or slot (shown in FIG. 25) through which the distal end of theplunger 3 can be inserted.

The syringe lock end 5 includes a holding slot 6 for receiving a syringe36 and an opening 41 through which the plunger 3 can pass. As shown inFIG. 23, the holding slot 6 is shaped like a barrel-wing. To secure asyringe to the syringe lock end 5, a proximal end of a syringe can beintroduced into the holding slot 6. In some embodiments, the proximalend of the syringe can be barrel-wing shaped such that when the syringeis introduced to the syringe lock end 5, the syringe comes into contactwith walls 34 of the holding slot 6. The syringe can then be rotated sothat it is securely received in the holding slot 6. One skilled in theart will appreciate that the holding slot 6 and the proximal end of thesyringe need not be shaped similarly. Nor is it necessary for theholding slot 6 to be barrel-wing shaped; any shape is suitable so longas it can receive a syringe end prior to rotating and securing of thesyringe.

The hollow body 7 of the adapter 1 is designed to receive the syringeplunger 3 as it moves transversely substantially along a longitudinalaxis of the hollow body 7 during injection. In some embodiments, thelength of the hollow body 7 of the adapter is between 2 and 5 inches.The hollow body can be circular, elliptical or any other shape suitablefor receiving the plunger 3. The diameter of the hollow body 7 can be,in some embodiments, between 0.5 and 1.1 inches.

FIG. 24 illustrates a front perspective view of the adapter 1 in FIG.22, including the opening 41 through which the plunger 3 can bereceived. Also shown are walls 34 of the syringe lock end 5. The walls34 are shaped such that upon initial entry of a syringe into the syringelock end 5, surfaces of the syringe 36 are placed into contact with thewalls 34. Upon rotation of the syringe 36, the syringe 36 can be lockedinto place in the holding slots 6.

FIG. 25 illustrates a rear perspective view of the adapter 1 in FIG. 22,including the adapter lock end 4 and flanges 25 receivable in theholding segment 33 of dispenser gun 2. Also illustrated is hole oropening 9 through which the plunger 3 can pass during the injection ofvein-occluding substance.

FIG. 26 illustrates a cross-sectional view of the adapter 1 and itshollow body 7. From this view, it is possible to see the adapter 1 ashaving at least two separate diameters, an inner diameter (formed at theopenings to the hollow body 7) and an outer diameter (formed in thehollow body 7 itself). In some embodiments, the inner diameter isbetween 0.5 and 0.9 inches, while the outer diameter is between 0.7 and1.1 inches.

FIG. 27 illustrates a side view of a glue gun system including anadapter 1, a glue gun 2, and a plunger 3 according to anotherembodiment. The system includes an adapter lock end 4 and a syringe lockend 5 having a syringe 36 attached thereto. In contrast to the system inFIG. 22, the glue gun system in FIG. 27 does not include an adapter lockend 4 having an exposed collar or flange that is placed in a holdingsegment of the gun 2. Instead, the adapter lock end 4 includes a flange25 (shown in FIG. 29) that mates with the glue gun 2 and remainsunexposed upon final assembly.

FIG. 28 illustrates a side view of the glue gun and adapter system ofFIG. 27 including the adapter 1, the glue gun 2, the plunger 3, and inaddition, a delivery catheter 200. In some embodiments, the deliverycatheter 200 includes an outer catheter surrounding an inner catheter.The delivery catheter 200 extends from the distal tip of the syringe 36and is designed to provide access to a target site within a vesselinterior.

FIG. 29 illustrates a perspective view of the adapter 1 in FIG. 27having an adapter lock end 4, a syringe lock end 5, a hollow body 7 anda fit-in notch 8 located near the adapter lock end 4. The fit-in notch 8is capable of receiving a mateable collar or flange located on the gluegun 2 that will lock the adapter 1 to the glue gun 2 upon rotation ofthe adapter.

FIG. 30 illustrates a front perspective view of the adapter 1 of FIG.27, including the syringe lock end 5. An opening 41 located on thesyringe lock end 5 is also shown. The opening 41, which is configured toreceive a dispenser plunger 3, is T-shaped in some embodiments, althoughsingle slit, “I”, arcuate, or other shaped openings are also possible.The advantage of the T-shaped opening 41 is that it can provide betterguidance for a dispenser plunger 3 that is received through the syringelock end 5, as the T-shaped opening provides specific paths along the“T” shape for the plunger 3 to move. The T shape can also add strengthto the plunger 3, such as in the longitudinal direction, for moreefficient dispensing. The T shape also could add stability to theplunger 3 in the transverse direction to increase its buckling strengthso that it will be less likely to buckle during the dispensing of highviscosity materials.

FIG. 31 illustrates a rear perspective view of the adapter 1 of FIG. 27,including the adapter lock end 4. The adapter lock end 4 includes itsown T-shaped opening 9, similar to the T-shaped opening 41 in thesyringe lock end 41, through which dispenser plunger 3 can pass.

FIG. 32 illustrates a cross-sectional view of the adapter 1 of FIG. 27and its hollow body 7. The adapter 1 includes a central lumen 7 withopen proximal and/or distal ends and designed to allow the syringeplunger 3 to move through during the injection process. The adapter 1also can optionally include one, two, or more side lumens 10 definedbetween walls 70 and 72, which can provide the adapter 1 with a reducedweight, which can be beneficial in some circumstances. In someembodiments, the side lumens 10 define a closed free space volume thatis at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or moreof the entire enclosed volume between walls 70, 72. By providing anadapter with reduced weight, this allows for improved handling, reducedweight, and cost efficiencies for manufacturing purposes. In otherembodiments, the adapter 1 can include regions besides or in addition tothe second hollow space 10 that are removed or cut-out of the adapter 1to provide additional weight reduction.

FIG. 33 illustrates an adapter 1 and glue gun 2 prior to assembly. Insome embodiments, the glue gun 2 includes extensions 66 that enclose anopen space 67 for receiving the adapter lock end 4 of the adapter 1.While the adapter lock end 4 is placed in the open space 67, theextensions 66 of the glue gun 2 enclose the fit-in notch 8 of theadapter 1, thereby forming a secure connection between the adapter 1 andglue gun 2, as shown in FIG. 34.

FIG. 34 illustrates the adapter 1 and glue gun 2 of FIG. 33 followingassembly. Included in the assembly within the hollow body 17 of the gluegun are plunger 3 with teeth 16, stopper 11, spring mechanism 15including spring pin 13 and spring pawl 14, plunger release button 18,floating gripper 19, plunger pocket 20 and spring stop 21.

As shown in FIG. 34, the assembly includes a glue gun 2 having a trigger12 for controlling the dispensation of glue from the gun. The trigger 12of the glue gun is integrated with the gun body by a spring pin 13,which is part of a spring mechanism 15. The spring mechanism 15 alsoincludes a spring pawl 14 designed to interact with teeth 16 of theplunger 3 to precisely lock the position of the plunger. Movement of thespring pawl 14 is controlled by the trigger 12. Upon pressing orclicking of the trigger, the spring pawl 14 is adjusted to allow one ormore teeth 16 of the plunger 3 to move forward through the adapter 1 andpress against a syringe (not shown) to dispense a glue or adhesive. Toprevent the rearward movement of the plunger 3 after clicking thetrigger, a floating gripper 19 is provided that engages with the plunger3 to stop rearward movement by frictional force. Plunger pocket 20 canallow movement (both forward and backward) of floating gripper 19 in thepocket. During the forward movement of the plunger 3, the floatinggripper 19 moves with the plunger 3 (because of the friction betweenthem) assisted by the plunger pocket 20. After the trigger is releasedand the plunger 3 (with the floating gripper 19) moves backward, theplunger pocket 20 sets the limit for the movement of the plunger 3. Theplunger release button 18 allows the disengagement between the plunger 3and the spring pawl 14. Pushing the plunger release button 18 will movethe spring pawl 14 downward and release the plunger 3 from the springpawl 14. Then the plunger 3 will be free to move in either backward orforward directions.

To limit the effect of the spring mechanism 15 and restrict the forwarddisplacement of the plunger teeth 16, the spring mechanism 15 isaccompanied by a stopper 11. The stopper 11 serves as a physical barrierto the movement of the spring mechanism, thereby providing for greatercontrol over dispensation of the glue or adhesive.

FIG. 35 is a front view of the glue gun 2 that illustrates the gunhollow body 17. Among the mechanisms within the gun hollow body 17includes the plunger 3, which is displaced within the hollow body by thepull of the gun trigger.

The embodiments of the glue gun system described in FIGS. 22-35 aredesigned to deliver precise amounts of adhesive or similarvein-occluding substance and can be used with the methods describedabove. By providing greater control over the dispensation ofvein-occluding substance, such as by using a spring mechanism 15including spring pawl 14 and stopper 11, the glue gun system can deliverthe vein-occluding substance continuously or in discrete injectablequantities, such as 0.1 ml to 1.0 ml per injection, therebyadvantageously reducing the risk of overflow and back-clogging of thedelivery system. The amount of vein-occluding substance used can dependon the size of the vein, the compression pressure, and surroundingenvironment. The glue gun will allow for exact increments of adhesive tobe extruded or discharged from a catheter. This will allow a vein to besealed shut at multiple sites along its length.

Deployable Occlusion Device

Embodiments are now described that relate to components of a venousocclusion system comprising a deployable occlusion device. FIG. 36schematically illustrates components that can be used in a venousocclusion system, according to one embodiment of the invention. Thesystem can include, for example, a deployable occlusion device 100 forinsertion into a desired location within a vein; a catheter 200 whichcan be a tubular member for delivering the occlusion device 100 as wellas serving as a conduit for delivery of one or more substances forclosing the vein; and an injector 300 that can be coupled to thecatheter 200 and actuating the substance into the vein via the catheter.

FIGS. 37A-D illustrate various views of one embodiment of a vascularocclusion device 100, according to one embodiment of the invention.Although certain particular embodiments of an occlusion device will bedescribed in detail herein, one of skill in the art will appreciate thatany of a variety of occlusion devices can be utilized in the system ofthe present invention. In some embodiments, the occlusion device can betransformable from a first, reduced cross-sectional configuration fortransluminal advance to the deployment site, to a second, radiallyenlarged or transversely enlarged configuration for occluding the vein.Transformation from the reduced configuration to the enlargedconfiguration can be accomplished in a generally radially symmetricalfashion, or in an elliptical, or planar fashion, each of which canaccomplish the result of achieving localized closure of the tubularstructure such as a vein in which the device is deployed. However, insome embodiments, the occlusion device 100 can be a vein-occludingsubstance, e.g., a bolus of glue, as will be described further below.

Transformation of the occlusion device may be accomplished in any of avariety of ways, such as by releasing a restraint on a frame which isbiased in the direction of the enlarged configuration. Alternatively,the occlusion device may be transformed to the enlarged configurationunder active force, such as by axial shortening to achieve radialexpansion. As a further alternative, occlusion devices for use with thesystem of the present invention may include detachable inflatableballoons, open cell or closed cell foam, sponge, embolic coil mesheshaving either a randomized or predetermined pattern, or other structuresdepending upon the desired clinical performance. The occlusion devicemay be provided with one or two or more tissue anchors or barbs, forengaging the vessel wall, or other anti-migration surface features suchas a roughened or adhesive surface, and/or enhanced surface area forcontact with the vessel wall in a manner sufficient to inhibitmigration.

FIG. 37A is a perspective view of an occlusion device 100 that includesa frame portion 102 and a barrier portion 106. The occlusion device isshown in a reduced, low crossing profile configuration for delivery,such as within a catheter 200. The frame portion 102 as shown has aproximal end 103 and a distal end 105, and can include at least 2 or 3or 6 or 8 or more interconnected struts 106 as shown.

The frame 102 may have a wide variety of wall patterns depending on thedesired clinical result, or have a continuous sidewall in someembodiments. In the illustrated embodiment, the wall pattern comprises agenerally sinusoidal framework including a plurality of proximallyfacing apexes 112 and distal apexes 110 interconnected by a plurality ofstruts 114. This can be clearly seen, for example, in FIG. 39B.

The frame portion 102 can be made of a metal, such as stainless steel,or a shape memory material such as, for example, nitinol or elgiloy.However, in some embodiments, the frame portion 102 may be made of ashape memory polymer or biodegradable material, such as, for example,poly(alpha-hydroxy acid) such as poly-L-lactide (PLLA); poly-D-lactide(PDLA), polyglycolide (PGA), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxide copolymers, modifiedcellulose, collagen, poly(hydroxybutyrate), polyanhydride,polyphosphoester, poly(amino-acids), or related copolymers. In someembodiments, the frame portion 102 can be laser-cut out of a tube. Ifthe frame portion 102 is biodegradable, it can be configured to fullydegrade over a period of time depending on the desired clinical resultand the properties of the vein-occluding substance (e.g., hardening orpolymerization time of a glue), such as, for example, less than about 1year, 6 months, 3 months, 1 month, 2 weeks, 1 week, 3 days, 1 day, 12hours, 6 hours, 3 hours, or less.

The barrier portion 104 can be sized, shaped, and attached to the frame102 in a variety of ways such that when deployed in an expandedconfiguration in the blood vessel, the occlusion device 100 preventsblood flow through the vessel. In some embodiments, the barrier 104 iscoupled to the frame 102 via sutures, adhesives, clips, or other form ofattachment. The barrier 104 may be made of any appropriate biocompatiblematerial suitable for occluding a vessel, such as a mesh. In someembodiments, the barrier 104 may be made of nitinol, elgiloy, Dacron®,Gore-Tex®, nylon, TFE, PTFE, ePTFE, peritoneum, subintestinal submucosaor other synthetic or biological membrane. Further materials that can beused for both the frame 102 and barrier 106 portions can be found, forexample, in U.S. Patent Pub. No. 2007/0292472 A1 to Paul et al., whichis hereby incorporated by reference in its entirety.

FIG. 37B illustrates a side view of the occluder illustrated in FIG.37A. FIG. 37C illustrates a section through line A-A of FIG. 37B,showing the barrier 104 as well as frame 102. FIG. 37D is an end view ofthe device illustrated in FIGS. 37A-37C.

While the above occlusion device 100 is described as having a frameportion 102 and a barrier portion 104, various other occlusion devicesto prevent blood flow through the vessel lumen are also within the scopeof the invention, such as plugs, sponges, coils, adhesives,prothrombotic agents, and the like.

In the embodiment illustrated in FIG. 37A-37D, the axial length of theframe when in the compressed configuration is generally within the rangeof from about 5 mm to about 30 mm, or about 10 mm to about 20 mm in someembodiments. The outside diameter of the frame when compressed withinthe catheter is generally no greater than about 8 French, and preferablyno greater than about 4 French in some embodiments. The maximum outsidediameter of the occlusion device when in an unconstrained expansion isgenerally within the range of from about 2 mm to about 16 mm, or about 4mm to about 12 mm in some embodiments.

FIGS. 38A-38D illustrates the occlusion device 100 of FIGS. 37A-37D in adeployed configuration. As noted above, the occlusion device 100 may bemade of a shape memory material to facilitate self-expansion of thedevice from a reduced to an enlarged configuration. In otherembodiments, the device 100 is balloon-expandable. As shown, thediameter of proximal end 103 of the device 100′ expands to greater thanthat of the distal end 105 in order to engage the vessel wall andocclude the vessel. In some embodiments, the diameter of the proximalend 103 expands to at least about 110%, 120%, 130%, 140%, 150%, 200%, ormore of its diameter in an undeployed configuration. In someembodiments, the device 100 includes, such as on its proximal end 103,one or more retention structures for retaining the device 100 in thevessel wall. In some embodiments, a plurality of barbs or other anchorsare provided, for engaging adjacent tissue to retain the occlusiondevice 100 in its implanted position and to limit relative movementbetween the tissue and the occlusion device 100. The anchors areprovided on one device 100. The anchors are provided on one or more ofthe struts 106, or other portion of frame 14. In some embodiments, everystrut, every second strut, or every third strut are provided with one ortwo anchors each, or more. The anchor can be in a form or a barb, spike,or other appropriate configuration for securing the occlusion device 100to the vessel wall, as illustrated in greater detail in FIG. 40 below.

FIGS. 39A-39B illustrate an embodiment of the frame 102 portion of thedelivery device described above in connection with FIGS. 2A-3D in itsundeployed (FIG. 39A) and deployed (FIG. 39B) configurations with thebarrier portion 104 omitted for clarity.

FIG. 40 is a side cross-sectional view of an occlusion device 100 in anexpanded configuration and implanted within vessel 400. As previouslydescribed, the occlusion device 100 has a proximal end 103, distal end105, and one or more anchors 112 to limit relative movement between theocclusion device 100 and the vessel wall 400. The device 100 may haveany number of anchors depending on the desired clinical result, such asat least 1, 2, 3, 4, 5, 6, or more anchors.

FIG. 41 is a longitudinal cross-sectional view of an occlusion device100 such as that illustrated in FIG. 40, and in an undeployedconfiguration within a delivery catheter 200. Delivery catheter 200includes an inner catheter member 204 and an outer catheter member 202.Occlusion device resides within a lumen of outer catheter member 202.Relative movement of inner catheter member 204 relative to outercatheter member 202, such as retraction of outer catheter member 202relative to inner catheter member 204 or pushing of inner cathetermember 204 distally relative to outer catheter member 202 can facilitatedeployment of the occlusion device 100 within the vessel 400. Innercatheter member 204 may comprise a concentric tube, a push wire, orother structure capable of transmitting a deployment activating force.

Occlusion device 100 as shown is releasably attached to a detachmechanism 120 that allows for retraction and repositioning of theoccluder member prior to deployment. The detach mechanism 120 can be anyof a wide variety of mechanisms to provide releasable detachment, forexample, mechanical, chemical, or electrolytic detachment. Some examplesof mechanical detach mechanisms include a snare, suture loop, clip andthe like. The proximal end of the catheter preferably includes a luerlock or similar mechanism for coupling to a syringe or other injectorfor inserting a vein-occluding substance into the vein.

In some embodiments, after the occlusion device is deployed, avein-occluding material such as a sclerosing agent is injected into thevein. The purpose of the vein-occluding material can be to partially orcompletely destroy the endothelial cells lining the venous lumen, exposethe subendothelial collagen fibers within the vein, and ultimately forma fibrous cord. After the lining of the vein is damaged the vein can beforced closed by the use of compression stocking worn by the patients.Over time the damaged vein scars upon itself creating a completelyclosed vein. Endothelial damage is preferably as complete as possible,because otherwise, thrombus will form and layer endoluminally. Thepresence of a deployed occlusion device 100 advantageously preventsdistal embolization of the vein-occlusion substance distally past theocclusion device 100. Any vein-occluding material can be used dependingon the desired clinical result.

A wide variety of vein-occluding substances can be used. In someembodiments, the substance can include an adhesive such ascyanoacrylate, e.g., 2-octyl cyanoacrylate, and/or a sclerosing agentsuch as hypertonic saline, sodium tetradecyl sulfate, chromatedglycerol, tetracycline, talc, bleomycin, or polydocanol. Other adhesivesthat can be used include a biological glue such as a bovine serumalbumin-gluteraldehyde combination (e.g., BIOGLUE, Cryolife, Atlanta,Ga.). In some embodiments, a foam generated from, for example, one ormore of the above components can be used to enhance ablation and closureof the vein. The viscosity and air bubble mixture can also be controlledtaking into account the desired clinical result. Ultrasound or otherimaging modalities such as, for example, fluoroscopy, CT, or MRI can beused to observe and control distribution of the vein-occlusionsubstance. In some embodiments, foam or other micro-bubbles within thevein-occlusion substance can also serve as ultrasonic contrast. Furtherexamples of agents, methods, and devices for vein closure that can beused as well are described, for example, in U.S. Pat. No. 4,039,665 toFoley, U.S. Pat. No. 5,676,962 to Garrido et al., U.S. Pat. No.6,572,873 to Osman et al., U.S. Pat. No. 6,726,674 to Leu, U.S. Pat. No.7,314,466 to Lary et al., and U.S. Patent Pub. No. 2003/0206864 A1 toMangin, all of which are hereby incorporated by reference in theirentireties. In some embodiments, the invention can be practiced using acyanoacrylate based echogenic adhesive, visible under conventionalultrasound.

FIGS. 42-44 illustrate a cross-section of occlusion device 100 (withbarrier portion 104 not shown for clarity) in varying stages ofdeployment caused by relative movement of inner catheter 204 relative toouter catheter 202.

Using the systems and methods described herein provides little to norisk of injury to surrounding nerves or tissue, because the length ofthe treated vessel can be clearly identified without unnecessaryovertreatment. This is in contrast to many other procedures whichrequire, for example, that a catheter is placed superior to nerves whichmay be juxtaposed to the saphenous vein.

The vein closure system allows for a simple treatment for veins, such asabnormal refluxing varicose veins. The vein closure system includes thedelivery system and the unique intravascular adhesive. The procedure isless invasive, less painful, more effective and easier to recover fromcompared to existing treatments.

Although this application has been disclosed in the context of certainembodiments and examples, it will be understood by those skilled in theart that the present application extends beyond the specificallydisclosed embodiments to other alternative embodiments and/or uses ofthe application and obvious modifications and equivalents thereof.Additionally, the skilled artisan will recognize that any of theabove-described methods can be carried out using any appropriateapparatus. Further, the disclosure herein of any particular feature inconnection with an embodiment can be used in all other disclosedembodiments set forth herein. Thus, it is intended that the scope of thepresent application herein disclosed should not be limited by theparticular disclosed embodiments described above.

1. A method of treating a vein, comprising the steps of: advancing a catheter distally across a treatment zone in a vein; creating a first occlusion in the vein at a distal end of the treatment zone; introducing a first bolus of media into the vein against a proximal side of the first occlusion; creating at least a second occlusion in the vein, spaced proximally apart from the first occlusion; introducing a second bolus of media into the vein against a proximal side of the second occlusion; and withdrawing the catheter from the vein.
 2. A method of treating a vein as in claim 1, wherein the media comprises cyanoacrylate.
 3. A method of treating a vein as in claim 1, wherein the creating a first occlusion step comprises applying external pressure to the vein.
 4. A method of treating a vein as in claim 1, wherein the first bolus of media has a volume within the range of from about 0.05 to about 0.5 ml.
 5. A method of treating a vein as in claim 4, wherein the first bolus of media has a volume within the range of from about 0.1 to about 0.2 ml.
 6. A method of treating a vein as in claim 1, wherein the second bolus of media is introduced at a point spaced apart from the first bolus by a distance within the range of from about 2 cm to about 6 cm.
 7. A method of treating a vein as in claim 1 further comprising the step of applying external compression to the first bolus of media.
 8. A method of treating a vein as in claim 1, wherein at least one of the steps is performed under ultrasound guidance.
 9. A method of treating a vein as in claim 1, wherein at least one of the steps is performed under fluoroscopic guidance.
 10. A method of treating a vein as in claim 1, wherein introducing a first bolus of media is performed such that the media first travels distally within the vein toward the proximal side of the first occlusion, contacts the proximal side of the first occlusion, and then travels proximally within the vein, away from the proximal side of the first occlusion.
 11. A method of treating a vein, comprising the steps of: creating an occlusion in a vein; positioning the distal end of a catheter to define a first volume within the vein between the occlusion and the catheter; and introducing media from the catheter into the vein; wherein the media has a second volume that is at least about 110% of the first volume.
 12. A method of treating a vein, comprising the steps of: creating an occlusion in a vein; positioning the distal end of a catheter within the vein at a location proximal to the occlusion, the catheter having a distal opening and a side wall; and introducing media through the distal opening in a volume sufficient to advance proximally around the catheter between the sidewall of the catheter and the wall of the vein.
 13. A method of treating a vein as in claim 12, further comprising the steps of proximally retracting the catheter and repeating the creating an occlusion and introducing media steps.
 14. A method of treating a vein as in claim 12, wherein the volume sufficient to advance proximally around the catheter between the sidewall of the catheter and the wall of the vein is at least 0.1 mL.
 15. A method of treating a vein as in claim 12, wherein the vein is the saphenous vein.
 16. A method of treating a vein as in claim 12, wherein positioning the distal end of a catheter within the vein occurs less than about 3 cm distal to the superficial femoral vein junction.
 17. A method of treating a vein as in claim 12, wherein creating an occlusion in the vein comprises applying external compression in the vein.
 18. A method of treating a vein as in claim 13, wherein repeating the creating an occlusion and introducing media steps is performed at least about 3 times.
 19. A method of treating a vein as in claim 13, wherein repeating the creating an occlusion and introducing media steps is performed at least about 5 times.
 20. A method of treating a vein as in claim 12, wherein introducing media through the distal opening in a volume step is sufficient to advance the media at least 2 cm proximally around the catheter between the sidewall of the catheter and the wall of the vein. 